tbuckley/cabot-search huggingface dataset:
Synergistic activity of JAK2 and BCL-2 inhibition against B-cell acute lymphoblastic leukemia.
Authors: Sean Rinella, Nicholas Hess, Haley Bell, Lei Shi, Lixin Rui, Christian Capitini
Journal: Journal of Clinical Oncology (2023)

e22002 Background: Treatment of relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) remains a challenge particularly in patients who do not respond to traditional chemotherapy. The objective of this study was to assess the efficacy of fedratinib, a semi selective JAK2 inhibitor and venetoclax, a selective BCL-2 inhibitor, on a model of B-ALL using the human cell line RS4;11 in vitro and in vivo. While select studies have examined the efficacy of these drugs on hematologic disorders as single agents, data is lacking on whether these drugs work optimally as single agents or in combination. Methods: RS4;11 cells were treated with either vehicle (DMSO), single agent fedratinib or venetoclax, or the combination of both inhibitors for 48 and 72 hours. Live/dead discrimination was performed using flow cytometry and a 72-hour MTS assay to assess proliferation. Drug synergy was calculated using CompuSyn software to generate combination index (CI) scores, with a CI score less than 1 reflecting synergy. RS4;11 was then used in a cell line derived xenograft model using NSG mice. Peripheral blood was obtained via retroorbital bleeds on days +10 (engraftment), +21 (treatment start), and +35 (post treatment) to assess B-ALL disease burden. Mice were randomized to one of the following groups: untreated, single agent venetoclax, fedratinib, or combination therapy. Mice were treated for 14 days with 6.25 mg/kg venetoclax IP and 100 mg/kg fedratinib via gavage. Results: In vitro, the combination of 7.5 nM venetoclax and 700 nM fedratinib significantly increased cell death compared to single agent venetoclax (p = 0.0186) and fedratinib (p = 0.0035). Furthermore, the combination significantly decreased leukemia cell proliferation compared to single agent venetoclax (p = 0.0183) and fedratinib (p = &lt; 0.0001). Synergy between venetoclax and fedratinib was seen in combination (CI = 0.40517). In vivo, peripheral blood counts post treatment showed a significant decrease in leukemic burden in combination compared to both single agent venetoclax (p = 0.016770) and fedratinib (p = 0.00002). Flow cytometry analysis of peripheral blood also showed a significant increase in CD19 MFI expression in samples from mice that received either venetoclax or combination therapy. Conclusions: The combination of fedratinib and venetoclax synergistically combined to treat B-ALL in vitro. The combination also was effective at significantly reducing leukemic disease burden in a cell line derived xenograft model. Finally, the significant increase in CD19 MFI expression post treatment suggests this combination therapy may be useful as a bridge to other CD19 targeted cell therapies.
Opioid use, gabapentinoid use, and pain-related emergency department visits for patients living with advanced cancer.
Authors: Vikram Jairam, Meghan Lindsay, Pamela R. Soulos, Cary Philip Gross, Elizabeth Horn Prsic, Laura Van Metre Baum, Henry Soo-Min Park
Journal: Journal of Clinical Oncology (2023)

12119 Background: Regulatory efforts in response to the United States opioid epidemic have resulted in a decrease in opioid prescribing among oncologists and non-oncologists. Understanding how decreased opioid prescribing affects cancer-related pain can provide key insights into the downstream effects of these efforts. In this study, we explored temporal trends in opioid use, gabapentinoid use, and pain-related emergency department (ED) visits in older adult patients with advanced cancer and those without cancer. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER)-Medicare database from 1/1/2012 to 12/31/2017 to identify patients aged 66 years or older diagnosed with advanced solid tumor cancer (defined as stage IV and/or metastatic disease). A cohort of patients without a cancer diagnosis was identified using the Medicare 5% random sample. The three dependent outcomes assessed were opioid use, gabapentinoid use, and pain-related ED visits. Multivariable logistic regression was used to identify predictors of these outcomes and to calculate the predicted probability of each outcome for patients with and without cancer. We determined the absolute change in the predicted probability of each outcome from 2012 to 2017. Results: A total of 294,113 patients were included in the cohort; 45,899 (15.6%) with cancer and 248,214 (84.4%) without cancer. Between 2012 and 2017, the absolute change in predicted probability of opioid use declined less in the cancer [-6.1%; 68.6% to 62.5%] compared to the non-cancer cohort [-8.2%; 35.8% to 27.6%] (p&lt;.001 for difference). Gabapentinoid use increased more in the cancer [3.9%; 10.8% to 14.7%] than non-cancer [1.8%; 10.5% to 12.3%] cohort (p&lt;.001 for difference). There was no statistically significant change in pain-related ED visits in patients with cancer [0.6%; 12.4% to 13.0%] and a decrease in patients without cancer [-0.5%; 2.6% to 2.1%] (p=0.005 for difference). Conclusions: Our findings showed that opioid use decreased to a lesser degree among older patients with advanced cancer compared to patients without cancer, whereas gabapentinoid use increased to a greater degree among patients with cancer. There was no corresponding rise in pain-related ED visits, suggesting that these shifts in medication use may not have adversely affected this important outcome. [Table: see text]
The ticking “biological clock”: Reproductive assistance, costs, and elective fertility preservation in female oncologists and trainees.
Authors: Emily MacDuffie, Anna Lee, Aleksandra Kuczmarska-Haas, Shraddha Dalwadi, Erin F. Gillespie, Michelle Suzanne Ludwig, Emma Holliday, Fumiko Chino
Journal: Journal of Clinical Oncology (2023)

11001 Background: Women in medicine are often in training during their peak fertility years. Many women defer childbearing until after training due to career concerns; in consequence, female physicians experience a higher rate of infertility than the general population. Experiences of infertility among female physicians and attitudes towards fertility preservation have not been well described. Methods: A novel 39 question survey was designed after comprehensive literature review to collect cross-sectional data on attitudes toward family planning and utilization of assisted reproductive technology (ART) among self-identified US female oncologists of all career levels. Descriptive statistics summarized frequencies of responses. Results: A total of 1005 responses were collected from female oncologists, of which 811 (81%) were attending/practicing physicians and 194 (19%) were trainees (192 residents/fellows and 2 medical students). 32% reported experiencing infertility. Of these 318 women, 9% reported no out-of-pocket expenses for ART while 39% spent more than $10,000 and 20% spent ≥$30,000. Side effects from infertility treatment required missing work for 22% and another 25% suffered mental health concerns related to infertility. Elective cryopreservation of eggs or embryos was reported by 6% of attendings and 4% of trainees. Among the 25 attendings who reported plans/desire to undergo fertility preservation in the future, most (76%) were unsure of feasibility. This was similarly reported in 72% of the 32 trainees with plans/desire to pursue fertility preservation. More trainees than practicing physicians (73% vs 65%) felt that fertility preservation should be discussed during medical training. Similarly, more trainees than attendings (58% vs 47%) felt that fertility concerns have a negative influence of their decision on when to start a family. While only 5% of all respondents reported using fertility preservation, an additional 6% were planning/considering using it and 21% felt that it would have benefitted them had it been available and affordable during training. Of the group that felt it would have been beneficial, 52% had experienced infertility. Conclusions: A third of surveyed female oncologists report experiencing infertility. Those that seek reproductive assistance can incur significant out of pocket costs with treatment related effects that can disrupt work or cause mental health concerns. Although fertility preservation was used by very few, one in five felt it could have been helpful to them if it was available and affordable. These results underscore the need to better support women in medicine to reduce the impact of infertility for female oncologists.
Transforming growth factor-b1 and soluble co-inhibitory immune checkpoints as putative drivers of immune suppression in advanced basal cell carcinoma.
Authors: Bernardo Leon Rapoport, Ronald Anderson, Nonkululeko Malinga, Helen C. Steel, Pieter Meyer, Teresa Smit, Mahlatse Kgokolo
Journal: Journal of Clinical Oncology (2023)

9567 Background: BCC rarely metastasizes and the mortality rate is low; however, the disease is associated with substantial morbidity. Transforming growth factor-b1 (TGF-b1) is a key player in cell proliferation, differentiation, apoptosis, and immune regulation. TGF-b1 is associated with immunosuppression and resistance to immunotherapeutic drugs. Immune checkpoint proteins (ICMs) maintain self-tolerance and modulate the immune responses of effector cells. The current study compared the levels and possible associations between systemic soluble ICMs (sICMs) and a group of humoral modulators of immune suppressor cells in a cohort of patients with advanced basal cell carcinoma (BCC, n = 40) and a group of healthy control subjects (n = 20). Methods: We measured sICMs and immunosuppressive humoral modulators by using multiplex bead array or ELISA procedures, with plasma as the matrix. The sICMs comprised seven co-inhibitory (CTLA-4, BTLA, LAG-3, PD-1, PDL-1, PDL-2, and TIM-3) and eight co-stimulatory (CD27, CD28, CD40, CD80, CD86, GITR, GITRL, and ICOS) proteins, as well as the two dual-active sICPs, HVEM and TLR2. The seven humoral modulators of immunosuppressor cells included arginase 1, fibroblast activation protein (FAP), RANTES (Regulated upon Activation Normal T Cell Expressed and Presumably Secreted) also known as CCL5, interleukin-10 (IL-10), TGF-b1, and the M2-type macrophage biomarkers, soluble CD163 (sCD163) and sCD206. Ethics approval was granted by The Research Ethics Committee, Faculty of Health Sciences, University of Pretoria (Ethics Committee Approval Numbers 356/2020. Results: The plasma levels of six co-inhibitory sICPs, sCTLA-4, sLAG-3, sPD-1, sPD-L1, and sTIM-3 and sPD-L2 were significantly elevated in the cohort of BCC patients ( p&lt; 0.001- p&lt; 0.00001), while that of sBTLA was significantly decreased ( p&lt; 0.006). Of the co-stimulatory sICPs, sCD27 was significantly increased ( p &lt;0.0002) in the cohort of BCC patients, with the levels of the others essentially comparable with those of the control patients; of the dual active sICPs, sHVEM, sTLR2 was significantly elevated ( p&lt; 0.00001) and TLR2 comparable with the control group. Although the plasma levels of the seven modulators of immune suppressor function were not significantly different between the BCC and control groups, correlation heat maps revealed selective, strong associations of TGF-b1 with seven co-stimulatory (z = 0.618468-0.768131) and 4 co-inhibitory (z = 0.674040-0.808365) sICPs, as well as with sTLR2 (z = 0.696431). Conclusions: Notwithstanding the association of BCC with selective elevations in the levels of a large group of co-inhibitory sICPs, our novel findings also imply the probable involvement of TGF-b1 in driving immunosuppression in this malignancy, possibly via activation of regulatory T cells.
Assessment of how differences in efficacy and toxicity change healthcare professionals’ views on presentation of treatment options.
Authors: Marco Santos Teles, Malcolm David Mattes
Journal: Journal of Clinical Oncology (2023)

e18723 Background: Guidelines for improving healthcare delivery, and the patient experience, call for physicians to inform patients of all available treatment options with comparable efficacy. However, high level evidence comparing options is often unavailable, and “comparable” is subjective. This problem is compounded in oncology, since the main therapeutic modalities are all administered by different types of oncologists (surgical, medical, and radiation) whose cross-training in the risks and benefits of other modalities is incomplete. The purpose of this study was to determine how healthcare professionals’ views on which treatment options should be presented to a patient differ with variations in efficacy and toxicity. Methods: An electronic survey was sent to 1,683 physicians, trainees, nurses, therapists, researchers, and administrators at an NCI-designated Cancer Center. The survey asked participants to imagine being diagnosed with a potentially life-threatening medical disease that can be treated by two standard procedures: Procedure A performed by Doctor A or Procedure B performed by Doctor B. Participants were asked to rate the importance of Procedure B being presented as an alternative to Procedure A for several scenarios of varying cure rate and toxicity risk on a Likert-type scale ranging from 1 (Not at all important) to 5 (Extremely important). Descriptive statistics for all respondents, and subgroup analysis using the Mann-Whitney U and Kruskal-Wallis H tests, are reported. Results: 286 individuals responded (17% response rate). Table 1 shows the percentage of respondents who believed it very or extremely important that Procedure B be discussed as a reasonable alternative to A. On subgroup analysis, no significant difference between physicians (n = 65) and other healthcare professionals (n = 184) was observed for either scenario where the difference in efficacy was only 5%. However, when the difference in cure rate was large (80% vs. 50%), physicians were significantly less likely than all others to believe that discussing Procedure B was important, with mean Likert-type rating 2.55 vs. 2.99, respectively ( p= 0.023) if A and B had the same toxicity risk; 3.40 vs. 3.77, respectively ( p= 0.022) if A had higher toxicity; and 3.74 vs. 3.98, respectively ( p= 0.048) if A had risk of death. No significant differences were observed based on field of oncology (medical vs. surgical vs. radiation) or physicians’ stage of training (attending vs. resident/fellow). Conclusions: Most healthcare professionals favor a balanced discussion of treatment options across a range of differential efficacy, especially when there is also variable risk toxicity or death. [Table: see text]
Intensity at the end of life in pediatric neuro-oncology patients: The case for pediatric palliative care.
Authors: Chinwe Udemgba, Karen Sarah Hoehn, Wendy Shannon Darlington, Brett Palama
Journal: Journal of Clinical Oncology (2023)

10021 Background: Although pediatric cancer is rare, it is the leading cause of death by disease after infancy for children and adolescents in the United States. Children exist in the context of a family; hence, excellent care for a child must also include attention to the needs of the family. Palliative care aims to enhance quality-of-life for these children living with life threatening illnesses and their families. Among pediatric cancers, brain tumors have high disease-related mortality rates; therefore, early introduction of palliative care to these patients is critical. This study aims to evaluate the association of palliative care during the terminal admissions of pediatric neuro-oncology patients and intensity of care provided at the end of life. Methods: Pediatric patients with brain tumors were identified using the Pediatric Health Information System (PHIS). Inclusion criteria were age &lt;18, diagnosis of brain tumor as defined by ICD-10 codes, discharged as deceased, and hospital admission between 1/1/2017 and 12/31/2021. Intensity of care measures included: pediatric intensive care unit (PICU) admission, mechanical ventilation, total parenteral nutrition (TPN), and extracorporeal membrane oxygenation (ECMO). Results: 567 patients met the inclusion criteria. 359/567 (63%) patients had an inpatient palliative care consultation during their terminal hospital stay. Patients receiving a palliative care consultation had a lower percentage of PICU admission (64.9 vs 83.2, p=&lt;0.001), mechanical ventilation use (51.0 vs 76.0, p=&lt;0.001), and TPN use (18.1 vs 25.5, p=0.027). There were no significant differences in length of stay (22.07 vs 22.25 days, p=0.181) and ECMO use (0.28% vs 1.92%, p=0.450). Conclusions: Pediatric patients receiving palliative care consultations during their terminal admission received less intense care while having comparable lengths of stay. Palliative care should be offered to all families, even with aggressive goals, to help incorporate quality of life and comfort in the treatment plan and to ensure bereavement support is available if needed. Similar to data in the adult palliative care literature, this data demonstrates reduced resource utilization among pediatric patients receiving palliative care. Palliative care has been shown to be a supportive service that has the potential to improve the quality of life of patients. The first step toward equitable healthcare is to ensure that all children with a potentially terminal cancer diagnosis have access to full supportive services, including palliative care.
LUNG-IST-127: A pilot phase II study of maintenance cabozantinib plus pembrolizumab for patients with metastatic squamous non-small cell lung cancer (sqNSCLC) with disease control following induction therapy.
Authors: Ryan Huu-Tuan Nguyen, Lucia Notardonato, Alicia Hulbert, Apurva Mallisetty, Frank Weinberg, Israel Rubinstein, Irene Juson, Cindy Chan, Li C. Liu, Zhengjia Chen, Lawrence Eric Feldman
Journal: Journal of Clinical Oncology (2023)

TPS9151 Background: First-line combination chemotherapy with pembrolizumab followed by maintenance pembrolizumab is the standard of care treatment for patients with metastatic sqNSCLC. This was established by the phase III KEYNOTE-407 trial, which demonstrated a median progression-free survival (PFS) of 6.4 months in the experimental arm. Despite these advances, there remains a need to continue to improve upon survival outcomes for these patients. Cabozantinib is a small-molecule inhibitor of multiple tyrosine kinsases including MET, VEGFRs, AXL, RET, and ROS, which are receptors involved in tumor cell-proliferation, angiogenesis, and immune cell regulation. Preclinical studies have demonstrated the ability of cabozantinib to modulate both adaptive and innate immune cells and to exhibit synergistic activity when used in combination with immune checkpoint inhibitors. We hypothesize that cabozantinib in combination with pembrolizumab in the maintenance phase of first-line treatment of metastatic sqNSCLC will prolong median PFS with a tolerable toxicity profile. Methods: LUNG-IST 127 is a pilot phase II, single-arm clinical trial of maintenance cabozantinib in combination with pembrolizumab for patients with metastatic sqNSCLC who achieved disease control following standard 1L induction therapy with chemotherapy and pembrolizumab. Thirty-six patients will be enrolled at 2 US sites to receive first-line induction therapy with carboplatin, nab-paclitaxel or paclitaxel, and pembrolizumab for four cycles. After induction therapy, those who have achieved disease control based on re-staging imaging will continue onto maintenance therapy with cabozantinib 40mg PO daily in combination with pembrolizumab 200mg IV every 3 weeks. The primary endpoint is PFS estimated by Kaplan-Meier methods with associated 95% confidence intervals. Based on an exploratory power analysis using an elevated one-sided alpha level of 0.40, we hypothesize that the proposed therapy will prolong median PFS from 6.4 to 9 months. Key secondary endpoints include overall survival (OS), overall response rate (ORR), and characterizing the safety and tolerability of cabozantinib in combination with pembrolizumab. Quality of life will also be measured with the EORTC QLQ-C30. Correlative endpoints include characterizing cfDNA from biofluids and assessing the change in circulating immune cells in different phases of treatment in association with PFS and OS. This trial would be the first to address whether there is clinical benefit in utilizing combination cabozantinib and pembrolizumab in the maintenance phase of treatment in metastatic sqNSCLC. Clinical trial information: NCT05613413 .
RET testing and treatment patterns among patients with aNSCLC in US clinical practice.
Authors: Eunice Kim, Jesse Sussell, Carmen Ng, Justin Nedzesky, Qing Zhang, Celina Ngiam, Aaron Scott Mansfield
Journal: Journal of Clinical Oncology (2023)

9091 Background: Biomarker testing, including for rearrangement during transfection (RET), is recommended and important in selecting efficacious targeted therapy for patients with advanced non-small cell lung cancer (aNSCLC). This retrospective cohort study characterized RET testing and treatment patterns among aNSCLC patients in clinical practice. Methods: We used the nationwide Flatiron Health electronic health record-derived de-identified database to select patients diagnosed with aNSCLC (stage ≥IIIB) from 2017-2022. We measured rates of RET testing (test result ≤90 days after advanced diagnosis). We used logistic regression to identify baseline characteristics predictive of timely testing. Finally, we described treatment patterns for patients with RET+ aNSCLC before and after the US approval of RET inhibitors. Results: Among 26,329 aNSCLC patients, rates of RET testing ≤90 days after advanced diagnosis increased from 25% (2017 Q1) to 73% (2022 Q1). Patients were less likely to receive RET testing within 90 days if they were Black (multivariate odds ratio [OR] 0.8) or Hispanic (OR 0.8) compared to White, or had Medicare (OR 0.9; all p&lt;0.001) compared to commercial insurance. Patients were more likely to receive RET testing within 90 days if they were in the highest socioeconomic quintile (OR 1.4), had de novo disease (OR 2.1), or no history of smoking (OR 1.3; all p&lt;0.001). Between 2017 and 2022, there were increases in the use of next-generation sequencing (66% to 89%) and blood samples for biomarker testing (25% to 49%) and a decrease in mean days from diagnosis to test result (33 to 28) for the first RET test among those who had testing within 90 days. Among all patients with aNSCLC tested within 90 days (n=12,275), 73 were RET+ and received 1L treatment ≤90 days after advanced diagnosis. The most common 1L treatments before (n=35) and after (n=38) RET inhibitor approval were chemotherapy (40%) and RET inhibitor (42%), respectively (Table). Conclusions: RET testing has increased over time, but certain patient subgroups are less likely to receive timely RET testing and therefore may not be optimally treated. Among patients with RET+ aNSCLC identified after RET inhibitor approval, only 42% were treated with a RET inhibitor in the 1L setting. These results suggest both disparities in access to RET testing and unmet medical need among patients with RET+ aNSCLC. [Table: see text]